Nitroimidazole derivatives potentiated against tumor hypoxia: Design, synthesis, antitumor activity, molecular docking study, and QSAR study.

A hypoxic environment occurs predominantly in tumors. During the growth phase of a tumor, it grows until it exceeds its blood supply, leaving regions of the tumor in which the oxygen pressure is dramatically low. They are virtually absent in normal tissues, thus creating perfect conditions for selective bioreductive therapy of tumors. To this aim, a novel series of cytotoxic radiosensitizer agents were synthesized by linking the nitroimidazole scaffold with oxadiazole or triazole rings. The majority of the compounds exhibited moderate to excellent antiproliferative activities toward HCT116 cell line under normoxic and hypoxic conditions. The structure-activity relationship study revealed that compounds containing the free thiol group either in the oxadiazoles 11a,b or the triazoles 21a,b-23a,b demonstrated the strongest antiproliferative activity, which proves that the free thiol group plays a crucial role in the antiproliferative activity of our compounds under both normoxic (half-maximal inhibitory concentration [IC50 ] = 12.50-24.39 µM) and hypoxic conditions (IC50 = 4.69-11.56 µM). Radiosensitizing assay of the four most active cytotoxic compounds 11b and 21-23b assured the capability of the compounds to enhance the sensitivity of the tumor cells to the DNA damaging activity of γ-radiation (IC50 = 2.23-5.18 µM). To further investigate if the cytotoxicity of our most active compounds was due to a specific signaling pathway, the online software SwissTargetPrediction was exploited and a molecular docking study was done that proposed cyclin-dependent kinase 2 (CDK2) enzyme to be the most promising target. The CDK2 inhibitory assay assured this assumption as five out of six compounds demonstrated a comparable inhibitory activity with roscovitine, among which compound 21b showed threefold more potent inhibitory activity in comparison with the reference compound. A further biological evaluation proved compound 21b to have an apoptotic activity and cell cycle arrest activity at the G1 and S phases. During the AutoQSAR analysis, the model demonstrated excellent regression between the predicted and experimental activity with r2 = 0.86. Subsequently, we used the model to predict the activity of the test set compounds that came with r2 = 0.95.

Exploration of antiproliferative potential of modified triazole-benzohydrazone scaffold: Multitarget approach.

A novel series of triazole-benzohydrazone hybrids was efficiently designed and synthesized as antiproliferative agents, targeting different kinases. All compounds were screened via the National Cancer Institute (NCI) against 60 cancer cell lines, where compounds 16, 17, and 18 exhibited growth inhibition percent (GI%) of various leukemia subpanels with values of 70.33%, 64.13%, and 76.03%, respectively. Compound 18 showed broad-spectrum antiproliferative efficacy toward most cancer cells, with outstanding potency regarding melanoma (MALME-3M GI% = 101.82%) and breast cancer cell lines (MCF7 GI% = 85.87%), while proving safe toward the WI-38 normal cell line, compared to doxorubicin. Multikinase investigation including vascular endothelial growth factor receptor 2 (VEGFR-2), mesenchymal epithelial transition factor (c-Met), proto-oncogene B-Raf, mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, and phosphoinositide 3-kinase was accomplished to reveal its plausible mechanism of action, giving the ultimate potency against both VEGFR-2 and c-Met with IC50 values of 0.055 and 0.042 µM, respectively, while displaying moderate to good inhibition concerning the remaining kinases. DNA binding capability was excluded using the methyl green colorimetric assay. Further, it exhibited both early and late apoptotic induction by about 16- and 9.4-fold over the control, respectively, triggering cell cycle arrest in the G2/M phase. Physicochemical properties and bioavailability radar plot inferred drug-likeness characteristics for compound 18. The molecular docking study assessed the binding pattern with the active sites of c-Met and VEGFR-2.

Modified Tacrine Derivatives as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Synthesis, Biological Evaluation, and Molecular Modeling Study.

To develop multitarget-directed ligands (MTDLs) as potential treatments for Alzheimer's disease (AD) and to shed light on the effect of the chromene group in designing these ligands, 35 new tacrine-chromene derivatives were designed, synthesized, and biologically evaluated. Compounds 5c and 5d exhibited the most desirable multiple functions for AD; they were strong hAChE inhibitors with IC50 values of 0.44 and 0.25 µM, respectively. Besides, their potent BuChE inhibitory activity was 10- and 5-fold more active than rivastigmine with IC50 = 0.08 and 0.14 µM, respectively. Moreover, they could bind to the peripheral anionic site (PAS), influencing Aß aggregation and decreasing Aß-related neurodegeneration, especially compound 5d, which was 8 times more effective than curcumin with IC50 = 0.74 µM and 76% inhibition at 10 µM. Compounds 5c and 5d showed strong BACE-1 inhibition at the submicromolar level with IC50 = 0.38 and 0.44 µM, respectively, which almost doubled the activity of curcumin. They also showed single-digit micromolar inhibitory activity against MAO-B with IC50 = 5.15 and 2.42 µM, respectively. They also had antioxidant activities and showed satisfactory metal-chelating properties toward Fe+2, Zn+2, and Cu+2, inhibiting oxidative stress in AD brains. Furthermore, compounds 5c and 5d showed acceptable relative safety upon normal cells SH-SY5Y and HepG2. It was shown that 5c and 5d were blood-brain barrier (BBB) penetrants by online prediction. Taken together, these multifunctional properties highlight that compounds 5c and 5d can serve as promising candidates for the further development of multifunctional drugs against AD.

Synthesis, Antitumor Activity, and In Silico Drug Design of New Thieno[2,3-d]Pyrimidine-4-One Derivatives as Nonclassical Lipophilic Dihydrofolate Reductase Inhibitors.

Synthesis of a new series of 20 compounds bearing the thieno[2,3-d]pyrimidine-4-one scaffold was achieved. The inhibitory activity of these compounds was performed over 60 cell lines of human tumor at single and five dose concentrations. Compounds 20, 22, and 23 exhibited potent growth inhibitions toward the majority of the tested NCI 60 cell lines. Compounds 20 and 23 were the most active compounds with (MG-MID) TGI, GI50, and LC50 values of 16.2, 3.3, 50.1 and 67.7, 6.6, 100, respectively. Also, both compounds showed 7- and 4-fold better activity, respectively, than the standard antitumor agent 5-fluorouracil. Therefore, compounds 20 and 23 were selected to measure their ability to inhibit the dihydrofolate reductase enzyme (DHFR) in comparison to methotrexate (MTX) as a reference drug. Compound 20 was a more potent inhibitor of DHFR (IC50 = 0.20 µM) than MTX (IC50 = 0.22 µM). Molecular modeling studies were performed in the DHFR active site, and it showed compatibility with the results obtained from biological studies. Finally, the results showed that compound 20 is a strong antitumor agent and potent inhibitor of DHFR. In addition, this compound induced cell-cycle arrest in SNB-75 cells in the G2/M phase and the apoptosis process in the Pre-G phase. Compound 20 also increased the level of both caspases-3 and 9 by 11.8- and 50.3-fold, respectively.

Insights into modulating the monastrol scaffold: Development of new pyrimidinones as Eg5 inhibitors with anticancer activity.

Based on modulation of the monastrol scaffold, two series of pyrimidinone derivatives, 3a-e and 5a-k, were designed, synthesized, and investigated for their in vitro anticancer activity. Compound 5j exhibited the most potent cytotoxic activity against four cancer cell lines, including HCT-116, HeLa, HEPG-2, and MCF-7, with IC50 values of 3.75-5.13 µM, while proving to be safe in the normal human cell line WI-38, with a selectivity index value of 13.7 on HCT-116 cells. Compounds 3d, 3e, and 5h-j were further assessed for their Eg5 inhibitory activity, where 3d and 5h-j showed high Eg5 inhibition with IC50 values of 28.48, 24.22, 18.90, and 12.89 µM, respectively, when compared to monastrol (IC50 = 14.89 µM). Cell cycle distribution of HCT-116 cells monitored with compound 5j illustrated that the cell cycle was arrested at the G2/M phase, with considerable apoptotic effect. A molecular docking study was performed to investigate the mode of action of the synthesized anticancer agents as Eg5 inhibitors.

Design, synthesis, and analysis of antiproliferative and apoptosis-inducing activities of nitrile derivatives containing a benzofuran scaffold: EGFR inhibition assay and molecular modelling study.

New cyanobenzofurans derivatives 2-12 were synthesised, and their antiproliferative activity was examined compared to doxorubicin and Afatinib (IC50 = 4.17-8.87 and 5.5-11.2 µM, respectively). Compounds 2 and 8 exhibited broad-spectrum activity against HePG2 (IC50 = 16.08-23.67 µM), HCT-116 (IC50 = 8.81-13.85 µM), and MCF-7 (IC50 = 8.36-17.28 µM) cell lines. Compounds 2, 3, 8, 10, and 11 were tested as EGFR-TK inhibitors to demonstrate their possible anti-tumour mechanism compared to gefitinib (IC50 = 0.90 µM). Compounds 2, 3, 10, and 11 displayed significant EGFR TK inhibitory activity with IC50 of 0.81-1.12 µM. Compounds 3 and 11 induced apoptosis at the Pre-G phase and cell cycle arrest at the G2/M phase. They also increased the level of caspase-3 by 5.7- and 7.3-fold, respectively. The molecular docking analysis of compounds 2, 3, 10, and 11 indicated that they could bind to the active site of EGFR TK.

Design, synthesis and molecular modeling of phenyl dihydropyridazinone derivatives as B-Raf inhibitors with anticancer activity.

Three new series of phenyl dihydropyridazinone derivatives 4b-8i have been designed, synthesized and evaluated for their anticancer activity against different cancer cell lines. Nine compounds showed strong inhibitory activity, among which compound 8b exhibited potent activity against PC-3 cell line with IC50 value of 7.83 µM in comparison to sorafenib (IC50 11.53 µM). Compounds 6a, 6c, 7f-h and 8a-d were further screened for their B-Raf inhibitory activity where seven compounds 7f-h and 8a-d showed high B-Raf inhibition with ranges of IC50 values 70.65-84.14 nM and 24.97-44.60 nM, respectively when compared to sorafenib (IC50 44.05 nM). Among the tested compounds, 8b was the most potent B-Raf inhibitor with IC50 value of 24.79 nM. Cell cycle analysis of MCF-7 cells treated with 8b showed cell cycle arrest at G2-M phase with significant apoptotic effect. Molecular modeling study was performed to understand the binding mode of the most active synthesized compounds with B-Raf enzyme.

1,2,3-Triazole-Chalcone hybrids: Synthesis, in vitro cytotoxic activity and mechanistic investigation of apoptosis induction in multiple myeloma RPMI-8226.

A new series of 1,2,3-triazole-chalcone hybrids has been synthesized and screened in vitro against a panel of 60 human cancer cell lines according to NCI (USA) protocol. Compound 4d having 3, 4-dimethoxyphenyl chalcone moiety, the most potent derivative, inhibited the growth of RPMI-8226 and SR leukemia cell lines by 99.73% and 94.95% at 10 µM, respectively. Also, it inhibited the growth of M14 melanoma, K-562 leukemia, and MCF7 breast cancer cell lines by more than 80% at the same test concentration. 4d showed IC50 values less than 1 µM on six types of tumor cells and high selectivity index reached to 104 fold on MCF7. Compound 4d showed superior activity than methotrexate and gefitinib against the most sensitive leukemia cell lines in addition to higher or comparable activity against the rest sensitive cell lines. Flow cytometry analysis in RPMI-8226 cells revealed that compound 4d caused cell cycle arrest at G2/M phase and induced apoptosis in a dose dependant manner. Mechanistic evaluation referred this apoptosis induction to triggering mitochondrial apoptotic pathway through inducing ROS accumulation, increasing Bax/Bcl-2 ratio and activation of caspases 3, 7 and 9.

Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors.

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.

Design, Synthesis and Anticancer Evaluation of New Substituted Thiophene-Quinoline Derivatives.

A series of new isoxazolyl, triazolyl and phenyl based 3-thiophen-2-yl-quinoline derivatives were synthesized adopting click chemistry approach. In addition, the synthesis of new useful synthon, (2-chloroquinolin-3-yl) (thiophen-2-yl) methanol, is reported. The obtained compounds were characterized by spectral data analysis and evaluated for their anticancer activity. All the derivatives were subjected to in vitro MTT cytotoxicity screening assay against a panel of four different human cancer cell lines, liver (HepG-2), colon (HCT-116), human cervical cancer (HeLa) and breast (MCF-7). Out of a library of 17 compounds, two compounds have been identified as potent and selective cytotoxic agents against HeLa and MCF-7 cell lines. SAR studies for such hybridized analogues were investigated and phenyl derivatives were proved to be more potent than isoxazole and triazole derivatives. Furthermore, the promising compounds were selected for in vitro inhibition of EGFR-TK and Topo II enzymes. Also, they were subjected to cell cycle arrest analysis and apoptosis assay on MCF-7 cells. Our recent finding highlights these thiophene-quinoline analogues as a promising class of compounds for further studies concerning new anticancer therapies.

Dihydrofolate reductase inhibition effect of 5-substituted pyrido[2,3-d]pyrimidines: Synthesis, antitumor activity and molecular modeling study.

A new series of pyrido[2,3-d]pyrimidines 3-18 bearing substitution at C-5 position was synthesized. All compounds were tested for their in vitro antitumor activity against five human cancer cell lines namely; hepatocellular carcinoma (HePG2), breast carcinoma (MCF-7), human prostate carcinoma (PC3), colorectal carcinoma (HCT-116), and cervical carcinoma (Hela) using doxorubicin as a positive control. Compounds 3, 4, 9, 11, 13, 14, 15 and 17 exhibited the highest antitumor activity against the tested cell lines and were selected to screen their enzymatic inhibition against dihydrofolate reductase enzyme (DHFR) compared with the reference drug methotrexate (MTX), to explain the probable mechanism of action of the observed anticancer activity. Compound 11 displayed the highest inhibitory activity (IC50 = 6.5 µM) among the tested compounds in comparison with MTX (IC50 = 5.57 µM). Also, compounds 13 and 14 showed high inhibitory activity against DHFR with IC50 values 7.1 and 8.7 µM, respectively. Comparative molecular modeling study was performed between DHFR inhibitors 11, 13 and 14 of the highest activity and 10 of the lowest activity among the eight inhibitors against MTX. Docking studies into the active site of DHFR domain showed good agreement with the obtained biological results. Finally, compound 11 was found to be best antitumor, DHFR inhibitor, and it induced the process of apoptosis at Pre-G phase and cell cycle arrest at G2/M phase in MCF-7 cells.

Design, synthesis and docking study of novel picolinamide derivatives as anticancer agents and VEGFR-2 inhibitors.

Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. All the new compounds were screened for their cytotoxic activity against A549 cancer cell line and VEGFR-2 inhibitory activity. Compounds 7h, 9a and 9l showed potent inhibitory activity against VEGFR-2 kinase with IC50 values of 87, 27 and 94 nM, respectively in comparison to sorafenib (IC50 = 180 nM) as a reference. Compounds 7h, 9a and 9l were further screened for their antitumor activity against specific resistant human cancer cell lines from different origins (Panc-1, OVCAR-3, HT29 and 786-O cell lines) where compound 7h showed significant cell death in most of them. Multi-kinase inhibition assays were performed for the most potent VEGFR-2 inhibitors where compound 7h showed enhanced potency towards EGFR, HER-2, c-MET and MER kinases. Cell cycle analysis of A549 cells treated with 9a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.

Synthesis and anticancer activity of new dihydropyrimidinone derivatives.

A series of dihydropyrimidinone derivatives bearing various N-heterocyclic moieties was designed and synthesized. Twelve new compounds were screened for their cytotoxic activity using 60 cancer cell lines according to NCI (USA) protocol. Compound 19 showed a significant activity against NCI-H460, SK-MEL-5, and HL-60 (TB) cell lines with growth inhibition 88%, 86% and 85%, respectively, and was found to be more safe on normal cells when compared to doxorubicin. Enzyme inhibition assay was performed for compound 19 against mTOR (IC50 = 0.64 µM) and VEGFR-2 (IC50 = 1.97 µM) to show high potency in comparison to rapamycin (IC50 = 0.43 µM) and sorafenib (IC50 = 0.3 µM) as references, respectively. Cell cycle analysis of A549 cells treated with 19 showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.

Design, synthesis, and molecular modeling of heterocyclic bioisostere as potent PDE4 inhibitors.

A new hybrid template was designed by combining the structural features of phosphodiesterase 4 (PDE4) inhibitors with several heterocyclic moieties which present an integral part in the skeleton of many apoptotic agents. Thirteen compounds of the synthesized hybrids displayed higher inhibitory activity against PDE4B than the reference drug, roflumilast. Further investigation indicated that compounds 13b and 20 arrested the cell cycle at the G2/M phase and the pre-G1 phase, and induced cell death by apoptosis of A549 cells in a caspase-dependent manner.

Enantioselective ruthenium-catalyzed 1,3-dipolar cycloadditions between C-carboalkoxy ketonitrones and methacrolein: solvent effect on reaction selectivity and its rational.

A catalytic 1,3-dipolar cycloaddition between carboalkoxy ketonitrones and methacrolein under the effect of chiral ruthenium Lewis acid (R,R-1) was developed with high regio-, diastereo-, and enantiocontrol. The diastereochemical outcome of the cycloaddition reaction is marked by a significant solvent effect, and a divergent endo or exo control can be tuned by an appropriate choice of both the solvent and the N- and O-substituents of the ketonitrone. A rationale of the solvent effect, based on the computational study of the interactions between the methacrolein-Ru complex and its counteranion (SbF6(-)), is proposed to explain the selectivities obtained.

Chiral N-heterocyclic carbene-copper(I)-catalyzed asymmetric allylic arylation of aliphatic allylic bromides: steric and electronic effects on γ-selectivity.

Chiral N-heterocyclic carbene ligands were electronically and sterically tuned to improve γ-selectivity in copper(I)-catalyzed asymmetric allylic arylation of aliphatic allylic bromides with several aryl Grignard reagents. High γ-selectivity was realized when either the aryl group of the Grignard reagent or the aryl group on the N-substituent of the carbene ligand was electron-deficient or when either the carbene ligand or allylic bromide was bulky. The results indicated that electron deficiency and steric hindrance of the initially formed σ-allyl copper intermediate enhance the rate of the reductive elimination to give γ-products as major isomers.

Copper-catalyzed asymmetric allylic substitution with aryl and ethyl Grignard reagents.

Phenyl- and ethyl-magnesium bromides undergo regioselective asymmetric allylic substitution with high enantioselectivity under the catalysis of chiral amidophosphane-copper(I) complexes.